In man, tuberculosis disease is highly associated with increased IL-10 production and the use of murine models has confirmed a critical role for IL-10 in disease progression. In this grant we propose to investigate how IL-10 can influence disease progression using both in vitro and in vivo techniques. We will take advantage of the CBA/J mouse strain which, in similarity to man, can naturally produce abundant IL-10 in vivo during infection with M. tuberculosis. Using the CBA/J mouse strain as our primary model we will determine the mechanism by which increased IL-10 production leads to disease progression by investigating the immune functions that are altered in the presence of this cytokine. In addition to investigating the natural progression of infection in a strain that produces abundant IL-10 we will also administer anti-IL-10R antibodies to determine exactly how IL-10 has a biological influence on disease progression. Furthermore, we will investigate whether blocking the action of IL-10 can reverse the susceptibility phenotype of this particular mouse strain, an event that would have particular relevance to the treatment and prevention of tuberculosis disease in man. The goal of this proposal is to use the CBA/J mouse strain as a tool to determine the in vivo role and relevance of IL-10 during infection with M. tuberculosis. This is best achieved using a mouse model in which abundant IL-10 production has been linked with disease progression. A more fundamental understanding of how IL-10 facilitates disease progression will provide critical information about the factors that contribute to an individual's susceptibility to develop active tuberculosis. Additionally, an understanding of the mechanism(s) by which IL-10 mediates disease progression would aid in the development of therapeutic treatments that may delay or even prevent tuberculosis disease.